Down-Regulation of PU.1 Gene in Pediatric Acute Lymphoblastic Leukemia Patients from South of Iran
AbstractBackground: Acute lymphoblastic leukemia (ALL) is resulted from the infiltration of high amount of non-differentiated cells in bone marrow. Differentiation of the hematopoietic stem cells into specific cell lineage occurs through a highly regulated pathway which is mainly monitored during transcription step. Expression level and pattern of transcription factors e.g. PU.1 determine fate and developmental phases in this pathway. This study was performed to evaluate the expression level of the PU.1 gene in a group of children suffering from ALL. Materials and Methods: The mRNA expression level of the PU.1 gene was compared between 30 children diagnosed as new cases of ALL and 30 sex- and gender-matched healthy children in the present case-control study. The quantitative real time PCR (qRT-PCR) was used to determine the level of PU.1 gene expression. The data were analyzed using Graph Pad Prism statistical software. Results: The mRNA level of the PU.1 gene was significantly lower in the blood samples of the ALL patients compared to the controls (p= 0.002). Conclusion: The results of the study indicated that the PU.1 gene seemed to have key roles in the differentiation pathway of blood cells.
Rieger MA, Schroeder T. Hematopoiesis. Cold Spring Harb Perspect Biol. 2012; 4. (12).
Eaves C, Cashman J, Eaves A. Defective regulation of leukemic hematopoiesis in chronic myeloid leukemia. Leuk Res. 1998; 22(12): 1085-96.
Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet (London, England). 2008; 371(9617): 1030-43.
Wilkinson AC, Gottgens B. Transcriptional regulation of haematopoietic stem cells. Adv Exp Med Biol. 2013; 786: 187-212.
Mak KS, Funnell APW, Pearson RCM, Crossley M. PU.1 and Haematopoietic Cell Fate: Dosage Matters. Int J Cell Biol. 2011; 2011.
Iwasaki H, Somoza C, Shigematsu H, Duprez EA, Iwasaki-Arai J, Mizuno S, et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005; 106(5): 1590-600.
Back J, Allman D, Chan S, Kastner P. Visualizing PU.1 activity during hematopoiesis. Exp Hematol. 2005; 33(4): 395-402.
Nutt SL, Metcalf D, D'Amico A, Polli M, Wu L. Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med. 2005; 201(2): 221-31.
Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990; 61(1): 113-24.
Blaybel R, Théoleyre O, Douablin A, Baklouti F. Downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival. Cell Res. 2008; 18: 834.
Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004; 36(6): 624-30.
Koschmieder S, Rosenbauer F, Steidl U, Owens BM, Tenen DG. Role of transcription factors C/EBPα and PU. 1 in normal hematopoiesis and leukemia. Int J Hematol. 2005; 81(5): 368-77.
Steidl U, Rosenbauer F, Verhaak RG, Gu X, Ebralidze A, Otu HH, et al. Essential role of Jun family transcription factors in PU. 1 knockdown-induced leukemic stem cells. Nat Genet. 2006; 38(11): 1269.
Metcalf D, Dakic A, Mifsud S, Di Rago L, Wu L, Nutt S. Inactivation of PU. 1 in adult mice leads to the development of myeloid leukemia. Proc Natl Acad Sci. 2006; 103(5): 1486-91.
Polgarova K, Vášková M, Froňková E, Slamova L, Kalina T, Mejstříková E, et al. Quantitative expression of regulatory and differentiation-related genes in the key steps of human hematopoiesis: The LeukoStage Database. Differentiation. 2016; 91(1): 19-28.
Mankaï A, Bordron A, Renaudineau Y, Martins-Carvalho C, Takahashi S, Ghedira I, et al. Purine-Rich Box-1–Mediated Reduced Expression of CD20 Alters Rituximab-Induced Lysis of Chronic Lymphocytic Leukemia B Cells. Cancer Res. 2008; 68(18): 7512-9.
Albajar M, Gutierrez P, Richard C, Rosa-Garrido M, Gómez-Casares MT, Steegmann JL, et al. PU. 1 expression is restored upon treatment of chronic myeloid leukemia patients. Cancer lett. 2008; 270(2): 328-36.
Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, et al. The myeloid master regulator transcription factor PU. 1 is inactivated by AML1-ETO in t (8; 21) myeloid leukemia. Blood. 2003; 101(1): 270-7.
Chen PM, Yen CC, Wang WS, Lin YJ, Chu CJ, Chiou TJ, et al. Down-regulation of Notch-1 expression decreases PU. 1-mediated myeloid differentiation signaling in acute myeloid leukemia. Int J Oncol. 2008; 32(6): 1335-41.
Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, et al. Heterozygous PU. 1 mutations are associated with acute myeloid leukemia. Blood. 2002; 100(3): 998-1007.
Bonadies N, Pabst T, Mueller BU. Heterozygous deletion of the PU. 1 locus in human AML. Blood. 2010; 115(2): 331-4.
Steidl U, Steidl C, Ebralidze A, Chapuy B, Han HJ, Will B, et al. A distal single nucleotide polymorphism alters long-range regulation of the PU. 1 gene in acute myeloid leukemia. J Clin Invest. 2007; 117(9): 2611.
Zhu X, Zhang H, Qian M, Zhao X, Yang W, Wang P, et al. The significance of low PU. 1 expression in patients with acute promyelocytic leukemia. J Hematol Oncol. 2012; 5(1): 22.
Wei S, Zhao M, Wang X, Li Y, Wang K. PU. 1 controls the expression of long noncoding RNA HOTAIRM1 during granulocytic differentiation. J Hematol Oncol. 2016; 9(1): 44.
Haimovici A, Humbert M, Federzoni EA, Shan-Krauer D, Brunner T, Frese S, et al. PU. 1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression. Cell Death Differ. 2017; 24(5): 866-877.
Li C, Tao Y, Li C, Liu B, Liu J, Wang G, et al. PU. 1–Bim axis is involved in Trichostatin A-induced apoptosis in murine pro-B lymphoma FL5. 12 cells. Acta biochimica et biophysica Sinica. 2016; 48(9): 850-5.